An immune response is initiated by presentation of antigen by class II MHC molecules to regulatory T cells. These T cells recognize the antigen-MHC complex via their T cell receptors (TcR). Activated T cells can then go on to help T-dependent B cell responses. Self-reactive T cells are eliminated in the thymus by mechanisms referred to as clonal deletion or kept in an anergic state in the periphery. The fate of T cells after the conclusion of a response is less clear, but a subpopulation remains as memory cells. This proposal will analyze the maternal immune response to fetal platelet alloantigens as a model system for B cell - T cell interactions in man. The initial focus will be on specific cases of neonatal alloimmune thrombocytopenic purpura (NATP) induced by an allotype of the integrin GPIIIa (PlA1). The response is characterized by generation of anti-PlA1 antibodies by a homozygous PlA2 mother and is predominantly restricted by the HLA-DRw52a class II MHC gene. This restriction is indicative of a role for T cells in the development of this predominantly B cell response. This form of NATP is interesting because of the directionality of the response. Anti-PlA1 responses are common whereas anti-PlA2 responses are infrequent and do not show a tight HLA restriction. The immunogenetic basis for NATP will be studied from two different points of view. First, it will be treated as an example of standard antigen presentation, where an antigenic peptide is presented by a restricted number of HLA alleles, and the B and T cell repertoires determine if the antigen can be recognized. Second, it will examine the possible role of DRw52 in eliminating T cells which may normally repress the anti-PlA1 response. This proposal will utilize novel molecular genetic techniques as well as classical immunologic manipulations to study T cell repertoires of women who have generated anti-PlA1 antibodies. These will be identified on the basis of complications in previous pregnancies and will be expanded to include family members who may be at risk. Important samples will be derived from women whose ensuing pregnancies do not show NATP or who have lost their anti-PlA1 titer. In addition, an animal model of NATP will be implemented using transgenic mice expressing the two allotypes of human GPIIIa. These studies should lead to an increased understanding of B-cell-mediated T-dependent autoimmunity which is important for transfusion and transplantation. They could lead to generation of reagents, such as specific anti-TcR monoclonal antibodies, which may be of therapeutic value, and can be expanded to include NATP due to other platelet alloantigens and other immune thrombocytopenias.